DESCRIPTION: (Adapted from applicant's description) Cytochrome P450 lAl (CYP 1A1), is involved in the bioactivation of a number of procarcinogenes, including aromatic amines and other hydrocarbons, important human lung carcinogens. This proposed pilot study focuses on the relationship between susceptibility to lung cancer risk and (a) human CYP 1A1 gene polymorphism and (b)CYP 1A1 enzyme inducibility phenotype, as well as (c) the molecular mechanisms involved in its induction by polycyclic aromatic hydrocarbons. The working hypothesis is that the measurements of CYP1A1 enzyme inducibility in HMLs may at least in part reflect the biological responses in the target lung tissue. Therefore, higher inducibility in human mononuclear cells (HMLs) may be a useful biomarker for human lung cancer risk assessment. The primary aim of this study is to compare P-450 lAl enzyme inducibilities in HMLs and lung alveolar epithelial cells and to determine their relationships to susceptibility to lung cancer. The secondary aim is to evaluate the usefulness of CYP 1A1 polymorphism in lung cancer risk assessment. In addition to the MspI polymorphism, a new PCR based method to detect polymorphisms not recognized by restriction enzymes will be also applied. There are at least-two forms of P-450 1A1 protein present in human lymphocytes dueto point mutation of the CYP 1A1 gene. This novel point mutation in genotype results in an amino acid substitution, which might affect enzyme inducibility phenotype and an individual's risk for oncogenic carcinoma. Finally, the relationship between enzyme inducibility and CYP 1A1 gene polymorphism will be also evaluated in order to understand more about the genetic regulation of CYP 1A1 and its relationship to human lung carcinogenesis. Lymphocytes and lung epithelial cells will be collected from an ongoing lung cancer case-control study with a total of 300 subjects (100 lung cancer patients and 200 controls). Inorder to improve the specificity and sensitivity of the measurement of P-450 lAl enzyme activities, the applicants have developed a new assay for 1Al, measured by using HPLC with a fluorescence detector. The assay has sensitivity at fmol range andis specific for lAl without interference of fluorescenceby other substances. Results from this pilot study can (1) provide useful information about the regulation of human CYP1A1 gene expression and its relationship to an individual's risk of bronchogenic carcinoma, (2) validate the potential usefulness of these biomarkers in human leukocytes as a surrogate to predict an individual's risk of bronchogenic carcinoma, and (3) lead to a more effective chemoprevention design for bronchogenic carcinoma in a large population-based longitudinal study planed in the applicant's Institute.